The EphB2 receptor (“EphB2” or “EphB2R”) is a member of the eph receptor family, which constitutes the largest family of tyrosine kinase receptors in the human genome (reviewed in Dodelet, Oncogene, 19: 5614-5619, 2000). The human eph receptor tyrosine kinases are categorized by sequence identity into an A class and a B class with corresponding A-type and B-type ligands referred to as ephrins. Signaling can occur in a forward manner, in which the receptor tyrosine kinase is activated by the ligand, and in a reverse manner, in which the transmembrane ephrinB ligands are activated by interaction with receptors. Eph receptor ligand interactions have been implicated in a wide range of biological functions including axon guidance, tissue border formation, vasculogenesis, and cell motility (Kullander et al. Nat. Rev. Mol. Cell. Biol., 3: 475-486, 2002; Cheng et al. Cytokine Growth Factor Rev., 13: 75-85, 2002; Coulthard et al. Int. J. Dev. Biol., 46: 375-384, 2002).
The EphB2 receptor has an extracellular region with a cysteine-rich motif extending over its amino-terminal half followed by two fibronectin type II motifs. There is an intracellular domain featuring a conserved kinase region and a transmembrane domain. EphB2 binds ligands such as ephrin-B1, ephrin-B2, and ephrin-B3. The cytoplasmic regions of the activated EphB2 receptor has been reported to interact with myriad familiar signaling molecules such as Src, Grb2, and Abl (Holland et al., EMBO J., 16: 3877-3888, 1997; Zisch et al., Oncogene, 16: 2657-2670, 1998; Yu et al., Oncogene, 20: 3995-4006, 2001). The EphB2 receptor tyrosine kinase down-regulates the ras/mitogen-activated protein (MAP) kinase signaling pathway and also inhibits the ab1 tyrosine kinase in endothelial and neuronal cells (Yu et al., Oncogene, 20: 3995-4006, 2001; Kim et al., FASEB J., 16: 1126-1128, 2002; Elowe et al. Mol. Cell. Biol., 21: 7429-7441, 2001).
Upregulation of both ephrin ligand and Eph receptor family members has been described in a range of human tumors and cell lines. For instance, EphB2 is reported to be over-expressed in small cell lung cancer (Tang et al., Clin Cancer Res 1999; 5:455-60), neuroblastomas, (Tang et al., Med Pediatr Oncol 2001; 36:80-2), melanoma (Vogt et al. Clin Cancer Res 1998; 4:791-7), breast carcinoma (Wu et al., Pathol Oncol Res 2004; 10:26-33), colorectal cancer (CRC) (Jubb et al., co-owned, co-pending U.S. patent application No. 60/642,164, filed Jan. 6, 2005, and Cairns et al., WO2003/000113) and hepatocellular carcinoma (Hafner et al., Clin Chem 2004; 50:490-9).
Antibody-based therapy has proved very effective in the treatment of various disorders. For example, HERCEPTIN™ and RITUXAN™ (both from Genentech, S. San Francisco), have been used successfully to treat breast cancer and non-Hodgkin's lymphoma, respectively. HERCEPTIN™ is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) proto-oncogene. HER2 protein overexpression is observed in 25-30% of primary breast cancers. RITUXAN™ is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Both these antibodies are produced in CHO cells.
The use of antibody-drug conjugates (ADC), i.e. immunoconjugates, for the local delivery of agents such as cytotoxic or cytostatic agents to kill or inhibit tumor cells in the treatment of cancer (Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Del. Rev. 26:151-172; U.S. Pat. No. 4,975,278) allows targeted delivery of the drug moiety to tumors, and intracellular accumulation therein, where systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated (Baldwin et al (1986) Lancet pp. (Mar. 15, 1986):603-05; Thorpe, (1985) “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,” in Monoclonal Antibodies '84: Biological And Clinical Applications, A. Pinchera et al (eds), pp. 475-506).
It is clear that there continues to be a need for agents that have clinical attributes that are optimal for development as therapeutic agents. The invention described herein meets this need and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.